DESCRIPTION (Investigator's Abstract): The goal of this research is to elucidate mechanisms by which the environment shapes the structure and function of brain cells through mechanisms that alter gene expression. Ovarian hormones are studied as mediators of environmentally-induced change because the PI's laboratory has discovered that estradiol (E) and progesterone (P) regulate cyclic synaptic plasticity. This plasticity occurs in the hippocampus, a brain region not previously known as a target area for reproductive hormones; in hippocampus, there is a cyclic synaptogenesis in CA1 pyramidal neurons regulated by ovarian steroids, as well as sexual differentiation of this response and also involving other aspects of hippocampal anatomy. The hippocampus is an attractive structure for investigation because of its anatomical organization and well-studied neuroanatomy and physiology. Moreover, with its role in episodic and spatial memory and its vulnerability to stress, aging, Alzheimer's disease and neurological insults, the hippocampus is a brain structure where particularly meaningful connections can be made between the rat brain and the human brain. In addition, the hormone effects on synaptic plasticity represent unique examples of inter-cellular communication, in that synaptogenesis is regulated by ovarian steroids acting in collaboration with excitatory amino acids via NMDA receptors. Because adult hippocampus, in contrast to hypothalamus, has few intracellular estrogen receptors (ER), which are found mainly in neurons that innervate the CA1 neurons where synapses are formed, the main hypothesis is that E induces de novo excitatory spine synapse formation by an integrated action on neuronal and glial elements that involves NMDA receptor regulation and regulated expression of specific synaptic and dendritic structural proteins as well as apolipoprotein E. In addition, it is hypothesized that this mechanism differs between males and females as a result of neuronal sexual differentiation. Experimental work will include establishing the role of classical ER or of non-genomic mechanisms in synaptogenesis, determining the role of NMDA receptors in the process, identification of estrogen-regulated gene products related to synapse formation and dendritic spine formation. Knock-out models of mice lacking genes will be used in order to test hypotheses about the role of ER, the synapsins and apolipoprotein E in synaptogenesis. Finally, the sexual differentiation of synapse formation and the role of androgen as well as estrogens in males will be investigated.